Node-positive prostate cancer represents 12% of newly diagnosed prostate cancer cases in the United States; with decreasing use of screening, this proportion is likely to increase. However, very few clinical trials have specifically compared treatment options for this group of patients. Radiotherapy has a potential role as both definitive therapy and adjuvant therapy for node-positive prostate cancer. In regard to definitive treatment, retrospective studies comparing androgen deprivation therapy (ADT) alone vs ADT plus radiotherapy consistently demonstrated better survival associated with radiotherapy. In addition, two secondary analyses of clinical trial data compared radiotherapy alone vs radiotherapy plus ADT in this setting, and showed combination treatment achieved better survival. In terms of adjuvant treatment after prostatectomy in the setting of pathologic node-positive disease, the Eastern Cooperative Oncology Group (ECOG) 3886 trial established ADT as a standard of care. Institutional retrospective studies showed that ADT plus radiotherapy was associated with improved overall survival compared with ADT alone, but an analysis of the population-based Surveillance, Epidemiology and End Results–Medicare linked data did not show a benefit from radiotherapy. Because current management is informed by mostly retrospective studies, clinical trials are needed to more definitively guide treatment decisions for patients with node-positive disease. Off trial, radiotherapy with ADT should be offered to patients with this very aggressive form of prostate cancer.
Among the 230,000 patients diagnosed with prostate cancer each year in the United States, 81% have localized cancer, 12% have node-positive disease, and 4% have distant metastatic disease (with the remainder unstaged). While there are numerous randomized trials to guide the management of patients with localized and metastatic cancers, few trials have specifically addressed node-positive patients—or even included any of these patients at all. As a result, there is uncertainty regarding the optimal treatment in this setting. Node-positive prostate cancer is categorized as “stage IV,” but patient management likely needs to be different from that for distant metastatic disease, and a proportion of node-positive patients are likely curable with aggressive multimodality therapy.
This article summarizes the existing literature on use of radiotherapy for node-positive prostate cancer, as well as the associated outcomes. Studies that examined the use of radiotherapy as definitive treatment (discussed below and outlined in Table 1) and as adjuvant therapy after radical prostatectomy (discussed below and outlined in Table 2) are reviewed separately.
Use of Radiotherapy as Definitive Treatment
Efficacy of androgen deprivation therapy (ADT) alone as treatment for node-positive prostate cancer
ADT alone is one treatment option for patients with node-positive prostate cancer. In the European Organisation for Research and Treatment of Cancer (EORTC) 30846 trial, 234 men with node-positive (pN1-3) prostate cancer were randomized from 1986 to 1998 to receive either immediate ADT or delayed ADT (given at time of clinical progression).[3,4] Patients were confirmed to be node-positive after lymphadenectomy, but no prostatectomy or other local treatment was performed. ADT consisted of either orchiectomy or treatment with gonadotropin-releasing hormone (GnRH) analog plus anti-androgen.
After a median follow-up of 13 years, the median overall survival (OS; 6.1 years with delayed ADT vs 7.6 years with immediate ADT) and 10-year prostate cancer–specific survival (44.4% for delayed ADT vs 47.9% for immediate ADT) were not statistically significantly different between the two arms. (P values were not reported.) Given these results, it is not clear if immediate ADT is better than a watch-and-wait approach for these patients.
Addition of definitive radiotherapy to immediate ADT
Definitive radiotherapy significantly improves OS over ADT alone for patients with locally advanced prostate cancer, as demonstrated by two randomized trials that compared ADT with ADT plus radiotherapy. The absolute survival benefit from radiotherapy in these trials was 8% to 10%.[5,6] Whether such benefit extends to patients with even more aggressive disease—node-positive prostate cancer—has not been definitively demonstrated. However, several retrospective studies provide support for a benefit from radiotherapy in these patients.[7-9]
In an analysis of patients treated at The University of Texas MD Anderson Cancer Center, Zagars et al compared the outcomes of 255 patients with staging lymphadenectomy–proven pathologically node-positive (pN+) disease who were treated with indefinite ADT alone (n = 183) vs ADT plus radiotherapy to a median dose of 68 Gy (n = 72). None of the patients had a prostatectomy. ADT consisted of either orchiectomy (58%) or medical castration (42%, using either a GnRH agonist or megestrol and diethylstilbestrol).
Patients who received ADT plus radiotherapy had better 10-year OS (46% for ADT alone vs 67% for ADT plus radiotherapy; P = .008), local control (49% vs 89%; P < .001), freedom from metastasis (56% vs 85%; P = .006), and freedom from recurrence (25% vs 80%; P < .001); however, patients treated with ADT alone had more aggressive cancers. On multivariate analysis, which adjusted for Gleason score, T stage, and pretreatment prostate-specific antigen (PSA) level, the addition of radiotherapy increased freedom from relapse or rising PSA (hazard ratio [HR] = 6.0; 95% confidence interval [CI], 3.1–11.5), freedom from distant metastasis (HR = 2.7; 95% CI, 1.3–5.6), and OS (HR = 2.1; 95% CI, 1.2–3.9).
Two studies analyzing data from SEER (Surveillance, Epidemiology and End Results) also suggest a survival benefit from radiotherapy. In a study from Tward et al, a total of 1,100 patients with node-positive disease diagnosed from 1988 to 2006 were included. The authors grouped both external beam radiation therapy (EBRT) and brachytherapy patients together, and compared them with a group that received no radiotherapy. After a median follow-up of 7.5 years, men who received radiotherapy had greater 5-year OS (56.2% for no radiotherapy vs 67.8% for radiotherapy; multivariate HR = 0.68; P < .01) and prostate cancer–specific survival (71.1% for no radiotherapy vs 78.1% for radiotherapy; multivariate HR = 0.67; P < .01). Another SEER analysis from Rusthoven et al showed improved 10-year OS and prostate cancer–specific survival in patients treated with radiotherapy vs no local therapy. It is important to note that SEER data do not definitively distinguish patients with clinical (radiographic) or pathologic (from biopsy or nodal dissection) node-positive disease, and no information on ADT is available.
Taken together, these retrospective studies have consistently demonstrated a survival benefit from radiotherapy compared with conservative management for node-positive prostate cancer, and suggest that definitive therapy with radiation is reasonable to consider. However, these studies are limited by their retrospective nature and patient selection factors that can potentially confound the comparisons. It is important to note, however, that patients with node-positive cancer, while stage IV, can achieve long-term survival; these retrospective studies strongly suggest that a proportion of patients are curable with aggressive therapy. Future prospective, randomized studies are needed to more definitively demonstrate the potential benefit of radiotherapy in node-positive disease. Current guidelines recommend either radiotherapy plus long-term ADT (2 to 3 years) or long-term ADT alone as treatment options.
Radiotherapy with or without ADT
For patients with high-risk and locally advanced prostate cancer, multiple randomized trials have demonstrated improved OS from adding ADT to definitive radiotherapy,[10-13] establishing this combination as a standard of care. Two of these trials included patients with node-positive disease, and subgroup analyses of these patients provide support for adding ADT to radiotherapy in this setting.
The Radiation Therapy Oncology Group (RTOG) 85-31 trial randomized 977 men with either T3 or node-positive disease to EBRT alone vs EBRT plus ADT. The ADT regimen was goserelin indefinitely or until progression, and radiotherapy was 65–70 Gy as definitive treatment or 60–65 Gy in the post-prostatectomy setting. In a subgroup analysis of the 173 patients with pathologic node-positive disease, the combined-therapy group had significantly better 5-year biochemical control (54% combined vs 10% for radiotherapy alone; P < .0001) and distant metastasis–free survival (P = .026; no percentages reported). OS was 72% for combined therapy vs 62% for radiotherapy alone (P = .23), but this subgroup analysis was not adequately powered to detect a survival difference. On multivariate analysis, radiotherapy alone compared with combined therapy was associated with increased overall mortality (HR = 1.62; P = .03), disease-specific failure (HR = 2.12; P = .014), metastatic failure (HR = 2.54; P = .0005), and biochemical failure (HR = 3.82; P < .0001).
Granfors et al randomized 91 patients to either EBRT alone or radiotherapy plus ADT. All patients underwent surgical lymph node staging (but not prostatectomy) prior to randomization, and 43% (n = 39) of patients were pathologic node-positive. The radiation dose delivered was 65 Gy, and androgen deprivation was achieved by bilateral orchiectomy. In a subgroup analysis of pathologically node-positive patients, after a median follow-up of 9.7 years, patients who received combined therapy had better OS compared with patients who received radiotherapy alone (log rank P = .005; percentages not reported).
With numerous randomized trials demonstrating a survival benefit from adding ADT to radiotherapy for patients with intermediate-risk,[16,17] high-risk, and locally advanced prostate cancers,[11-13,18-20] the results from these subgroup analyses of trials suggest that the benefit of adding ADT to definitive radiotherapy likely applies to patients with node-positive prostate cancer.
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